Ketamine and Phencyclidine Reward and Sensitization in Adult and Adolescent Rats

Dissociative drugs, a class that includes ketamine, phencyclidine and related drugs, are popularly abused, especially by teens and young adults in club and rave settings. Despite use by young people, little is known of the effects of these drugs in adolescents, and potential differences between adolescents and adults. The current thesis examined the effects of dissociatives in adolescents and adults in an animal model. Two behavioral responses, locomotor stimulation and ultrasonic vocalizations (USVs) were examined simultaneously following administration of ketamine or phencyclidine in adolescent and adult Sprague-Dawley rats. The effects of repeated administration were examined to determine if behavioral sensitization, a phenomenon that is characterized by an increase in the effect of a drug after repeated adminstration, occurs. Behavioral sensitization has been linked to drug addiction due to neural plasticity. USVs represent a new approach to measuring positive (reward) and negative (aversion) affective states. It was hypothesized that animals treated with ketamine or phencycline would show increases in locomotor activity and 50 kHz vocalizations, and that they will develop sensitization to both. Furthermore, it was hypothesized that adolescent animals would develop more rapid sensitization than adults, and the adolescents would show long-lasting effects of exposure to dissociatives when tested as adults. In Experiment 1, which examined ketamine, the first treatment induced a short-lived stimulant response that was greater in adolescents. Activity increased across days in adults and adolescents, reflecting the development of sensitization, with adolescents showing more rapid sensitization compared to adults. For 50 kHz USVs on Day 1 ketamine induced a short-lived response in adolescents, but not adults, and the adolescent group showed an upward trend in USVs across days, reflecting sensitization. In contrast, adults showed little evidence of sensitization to the USVs. Both adolescents and adults demonstrated persistent sensitization to locomotor behavior when tested 23 days later; only the adolescents showed persistent sensitization to USVs. In Experiment 2, which examined phencyclidine, the first treatment induced a stimulant response that was greater in adolescents. Locomotor activity increased across days for adults and adolescents, reflecting sensitization in both groups, with adolescents showing more rapid sensitization than adults. For 50 kHz USVs on Day 1 phencyclidine induced an increase in adolescents, but not adults. In contrast to our hypothesis USVs in adolescents decreased across days, reflecting the development of tolerance instead of sensitization. Both adolescents and adults demonstrated persistent sensitization in locomotor behavior. For USVs there was persistent tolerance in adolescents when tested 23 days later, but not in adults. The results demonstrate that adolescents are more sensitive to the stimulant and rewarding effects of dissociatives, and that changes following repeated use are dependent on the specific dissociative examined.